Esters and amides derivatives of α-(phenoxy)phenylacetic acids, such as halofenate, are chiral compounds and are useful in ameliorating a variety of physiological conditions, including conditions associated with blood lipid deposition, Type II diabetes and hyperlipidemia (see, e.g., U.S. patent application Ser. No. 10/656,567 and U.S. Pat. No. 6,262,118 which is incorporated herein by reference in their entirety). α-(Phenoxy)phenylacetic acids contain a single chiral center at carbonyl carbon atom, and therefore exist in two enantiomeric forms.
Cytochrome P450 2C9 is an enzyme known to play a significant role in the metabolism of specific drugs. It is known to one skilled in the art that changes in drug metabolism mediated by inhibition of cytochrome P450 enzymes has a high potential to precipitate significant adverse effects in patients. It is also known that a racemic α-(phenoxy)phenylacetic acid, e.g., halofenic acid, inhibits cytochrome P450 2C9 (see, e.g., U.S. patent application Ser. No. 10/656,567 and U.S. Pat. No. 6,262,118). Thus, administration of a racemic α-(phenoxy)phenyl-acetic acid, such as halofenic acid or its derivatives, can lead to a variety of drug interaction problems with other drugs, including anticoagulants, anti-inflammatory agents and other drugs that are metabolized by this enzyme. It has been found that the (−)-enantiomer of halofenic acid is about twenty-fold less active in its ability to inhibit cytochrome P450 2C9 compared to the (+)-enantiomer. Id. Thus, it is desirable to administer the (−)-enantiomer of halofenic acid or its derivatives which is substantially free of the (+)-enantiomer to reduce the possibility of drug interactions.
Therefore, there is a need for an efficient process for producing a product enriched in a desired enantiomer of a α-(phenoxy)phenylacetic acid, e.g., (−)-halofenic acid.